The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK2 is a well validated target with strong potential in the treatment of myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systematic mast cell disease. The strongest evidence for the link between JAK2 and MPDs is the prevalence of the V617F mutation in PV patients. The treatment of PV patients is currently considered non-optimal. A combination of phlebotomy and non-specific hematopoietic suppression with hydroxy urea is the current standard of care for PV patients. Other agents used to treat PV such as anagrelide and interferon-alpha, also require careful monitoring and elicit multiple side effects such as risk of leukemic progression, headache and gastrointestinal discomfort.
JAK3 has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematological malignancies such as leukemias and lymphomas.
Accordingly, there is a great need to develop compounds useful as inhibitors of protein kinases. In particular, it would be desirable to develop compounds that are useful as selective inhibitors of JAK2 for the treatment of myeloproliferative and other related proliferative disorders. In particular, selectivity against JAK3 would provide an adequate safety margin with respect to undesired immune suppression specifically mediated by JAK3.